Method for controlling insects and helminths with triazinyl compounds



United States Patent METHOD FOR CONTROLLING INSECTS AND HELMINTHS WITHTRIAZINYL COMPOUNDS Robert L. Goulding, Jr., Corvallis, Greg, and CarlR.

Tanner, Lafayette, Caliii, assignors to California Research Corporation,San Francisco, Calif, a corporation of Delaware No Drawing. Filed Aug.23, 1963, Ser. No. 304,217

Claims. (Cl. 167-53) This invention relates to a method for controllingparasites attacking warm-blooded domestic animals and for improving thegrowth characteristics of such domestic animals. More particularly, thisinvention concerns the use of phosphate esters of4,6-diamino-1,3,5-triazinyl compounds.

Domestic animals are subject to attack by a great variety of parasites.Such parasites as fleas, flies, lice, ticks,

screws-Worms, cattle grubs, ox warbles, as well as helmin-.

thic parasites, such as stomach worms and gastrointestinal worms, arewell known. Commercial losses due to loss of weight in the animal,injury to the hide, and mortality because of these parasites areextremely high. With pets, the lack of well being or the mortalitycannot be accounted for in dollars.

It has now been found that compounds of the following formula:

wherein R and R are lower alkyl and may be the same or different, and RR R and R are hydrogen or lower alkyl and may be the same or different,and X and Y are chalcogen of atomic number of 8 to 16 and may be thesame or dilferent (chalcogen is intended to be oxygen or sulfur), areeffective in the control of parasites which attack domestic warm-bloodedanimals.

Included in lower alkyl groups are methyl, ethyl, propyl, isopropyl,pen-tyl, isohexyl, etc.

Preferred compounds have the following formula:

4 N (R 0) 2 P-Y-CHgwherein R is lower alkyl from 1 to 2 carbons, i.e.,methyl or ethyl, R is hydrogen or lower alkyl from 1 to 2 carbons, i.e.,methyl or ethyl, and X and Y are either oxygen or sulfur.

Particularly preferred compounds have the following formula:

wherein R can be methyl or ethyl and is preferably methyl.

Compounds included within the generic scope of this invention are0,0-dimethyl S-(4-dimethylamino-6-amino- 1,3,5-triazin-2 yl)methylphosphorothioate, 0,0-diet-hyl S-(4,6-bismethylamino)-l,3,5-triazin-2-yl)methyl phosphorodithioate, 0,0 dipropylS-(4,6-bis-(diethylamino)- 1,3,5-triazin-2-yl)methyl phosphorothioate,etc.

The dosage to be used will depend on the animal to be treated, theparasite to be destroyed, the method of application, as well as theparticular compound used. High dosages are to be avoided for, at valuesmuch above those suggested, sporadic mortality occurs.

The triazinyl compounds used in this invention may be administeredorally or parenterally. When given orally, they may be in any convenientand customary oral form of medication, such as a capsule, tablet, or asa drench. They may :also be incorporated in the animals feed or drinkingwater. Moreover, they may be introduced into the body of the animal byhypodermic or intramuscular injection or may be absorbed through theskin by means of a dip, spray, or wash. The manner of administration ofthese compounds is not particularly important so long as the prescribedamounts of them are introduced into the body of the animal Where theymay be distributed throughout the body by the action of the circulatorysystem.

When the triazinyl compounds are orally administered, the total amounttobe applied will depend on whether the dose is given as a single dose oras multiple doses over a period of several days. With calves, in asingle dose, some improvement is found with 5 mg./kg. (When weight/weight is used as a unit, it is intended to signify unit weight oftriazinyl compound/unit weight of subject.) However, it is preferredthat at least 25 mg./kg. be used. The preferred range of dosage per calfis in the order of 25 to mg./ kg. Amounts in excess of 75 mg./ kg. haveoccasionally resulted in mortality of the subject. When using multipledosages, the dosage per day should probably not be less than /2 mg./kg.and preferably should be at least 3 mg./kg. When administering thetriazinyl compounds on succeeding days, the total dosage should probablynot exceed 75 mg./kg. With sheep and dogs, higher dosages than withcalves may be used. With sheep, a single dosage as high as mg./kg. maybe used. With dogs, even higher dosages may be used, particularly as atotal dosage when multiple administration is applied.

In the preparation of solid feed compositions, the compounds may bemechanioally mixed with a finely divided eatable, such as flour oranimal feed, or a solid surfaceactive dispersing agent, such as finelydivided bentonite, fullers earth or attapulgite. These compositions maybe administered in the form of capsules or tablets or dispersed in ananimal feed and such feed used to supply a part or the entire ration.Alternatively, the compounds may be dissolved in an organic solvent, theresulting mixture dispersed in an animal feed and the feed dried toremove the solvent material. Also, the compounds may be dispersed'in' aneatable oil, such as coconut oil, olive or peanut oil, and the resultingmixture dispersed in the feed.

As mentioned previously, the compounds may be applied parenterally.Spraying the animal with an aqueous dispersion or using a dip areillustrative of methods of applying the compounds used in thisinvention. The concentration of these compounds in the spray or dip mayvary widely, usually in the range of 0.25 to 10%, being dependent on thenecessity that a sufficient amount of the compounds be applied to thesubject. When using an aqueous dispersion, surface-active dispersingagents, such as ionic or nonionic emulsifying agents, may be used.Suitable surface-active dispersing agents include the glycerol andsorbitan esters of fatty acids, and the polyoxy- .3) The followingexamples illustrate the invention and are not to be construed aslimiting.

Example I A Hereford heifer weighing 510 pounds was treated with a closeof 0,0-dimethyl S-(4,6-diamino-1,3,5-triazin- 2-yl)methylphosphorodithioate (which shall be referred to as Menazon) 80 W.P. atthe rate of 75 mg. Menazon per kg. of body weight. Dosage was by meansof two orally administered gelatin capsules. At the time of treatmentthere were four warbles containg grubs nearly ready to drop and twentywarbles containing less mature individuals present in the back of thecalf. About 36 hours after treatment the heifer showed signs ofintoxication. However, after 4 days the animal began gradually to returnto normal. Twelve days after the treatment no live grubs were found inthe animal upon inspection. No grubs were found in this animal for thebalance of the annual grub season.

Example 11 Three Hereford heifers with an average weight of about 338pounds were sprayed with a 1.5% Menazon 80 W.P. solution at a pressureof approximately 100 psi. About 1.5 gallons/head was used to completelysaturate the hair coat. Two and one-half months later the controlsubjects showed an average of 7.2 grubs/head while the three calvestreated with Menazon were entirely grub free.

Example 111 Three Hereford heifers averaging about 340 pounds were fedan alfalfa meal-bran mix containing about 0.03% by weight concentrationof Menazon. The heifers were fed the Menazon fortified feed over a 6-dayperiod, the dosages averaging between about 7.8 and 9.8 mg./kg. About 60days later, while the controls showed an average of 7.2 grubs/head, thetreated calves were entirely grub free.

Example IV The calves in Example II were also checked for their lousepopulation. The long-nosed cattle louse, the little blue cattle louseand the biting louse were all present. With the sprayed calves inExample II, perfect control was obtained for greater than a 3-weekperiod. With the fed calves, almost perfect control was obtained for thesame period.

Example V To a 22 pound dog, infested with oriental rat fleas, wasadministered 50 mg./kg. of body weight of Menazon on 4 succeeding daysas part of the normal daily ration. With the fourth dose, 100% fleamortality was achieved.

In a similar test a 16 pound dog was fed with a Menazon fortified feedcontaining .25 g./lb. of feed. This resulted in a dosage ofapproximately 21 rug/kg, which was administered over a -day period. Twodays after the final dosage, 100% flea mortality was achieved.

Example VI Oriental rat'fleas were allowed to feed through nylon gauzeon rats which had been fed Menazon in the daily ration. The Menazon wasdissolved in a solution of 1 part acetone and 3 parts corn oil, and 0.5ml./100 gms. body weightwas administered to the rat. The fleas wereexposed to the rats for 24 hours and then held an additional 24 hoursbefore assessing mortality. By using varying dosages the L13 the dosagenecessary for 50% mortality in fleas, was found to be approximately 200mg./kg. of body weight. A comparable test with Ronnel, 0,0- d i m e t hy l O-(2,4,5-trichlorophenyl)phosphorothioate, showed an LD of 350mg./kg. of body weight.

{Menazon SO W.P. indicates a sample having 80% by weigglit of the activeingredient and formulated as a Wettable pow er.

Example V11 To a 5.1 kg. female dog was administered 15 mg./kg. per dayof '0,0-dimethyl S-(4-amino-6-methylamino- 1,3,5-triaZin-2-yl)methylphosphorodithioate on four succeeding days as part of the normal dailyration. About 2 hours following the second dose, two cells of 25 fleaseach were placed on the shoulders of the subject. The fleas were removedon the day following the fourth dose. They were held for 24 hours andmortality was determined on the basis of mortal responses. A fleamortality was observed as compared to a control of 10%.

Example VIII To a 7 kg. dog was administered 15 mg./kg. per day of0,0-dimethyl S-(4-amino-6-methylamino-l,3,5-triazin- 2-yl)methylphosphorothioate on four succeeding days as part of the normal dailyration. About 2 hours following the second dose, 2 cells of 25 fleaseach were placed on the shoulders of the subject. The fleas were removedon the day following the fourth dose. They were held for 24 hours andmortality was determined on the base of mortal responses. flea mortalitywas observed, as compared to a control showing only 10% mortality.

The use of the compounds of this invention provides an effective way ofcontrolling parasites which attack domestic warm-blooded animals. Totalmortality of the parasite may be achieved, with significant protectionmaintained for long periods of time.

This application is a continuation-in-part of copending applicationSerial No. 208,129, filed July 6, 1962, now abandoned.

As will be evident to those skilled in the art, various modifications onthis process can be made or followed, in the light of the foregoingdisclosure and discussion, without departing from the spirit or scope ofthe disclosure or from the scope of the following claims.

We claim:

1. A method for controlling insects and helminths attacking domesticwarm-blooded animals, which comprises introducing into the body of theanimal a chemotherapeutic dosage of G,O-dimethyl S-(4,6-diamino-l,3,5-triazin-2-yl)methyl phosphorodithioate.

2. A method for controlling insects and helminths attacking domesticwarm-blooded animals, which comprises introducing into the body of theanimal a chemotherapeutic dosage of a compound of the following formula:

wherein R and R are lower alkyl from 1 to 6 carbons, R R R and R areselected from the group consisting of hydrogen and lower alkyl of from 1to 6 carbons, and X and Y are chalcogen of atomic number of 8 to 16.

3. The method according to claim 2 wherein Y is sulfur.

4. The method according to claim 2 wherein X and Y are sulfur.

5. The method according to claim 2 wherein X and Y are sulfur and R andR are methyl.

6. The method according to claim 2 wherein X and Y are sulfur, R and Rare methyl and R R and R are hydrogen.

7. A method for controlling insects and helminths attacking domesticwarm-blooded animals, which comprises introducing into the body of theanimal a chemotherapeutic dosage of 0,0-dimethylS-(4-amino-6-methylamino-1,3,5-tn'azin-2-yl)methyl phosphorothioate.

8. A method for controlling insects and helminths attacking domesticwarm-blooded animals, which comprises introducing into the body of theanimal a chemotherapeutic dosage of 0,0-dimethylS-(4-amino-6-methylamino-1,3,5-triazin-2-yl)methyl phosphorothioate.

5 6 9. A method for controlling insects and helminths at- ReferencesCited by the Examiner tacking domestic warm-blooded animals, whichcomprises UNITED STATES PATENTS introducing into the body of the animala chemotherapeutic dosage of 0,0-diethy1 S-(4,6-bisrnethylamino-3,099,106 7/63 Edgar 1,3,5-triazin-2yl)methyl phosphorodithioate. 5OTHER REFERENCES A method for Controlling insects and helminths Frear:Pesticide Index, 1961, College Science Publishtacking domesticwarm-blooded animals, which comprises as, state c ll Pa page 1introducing into the body of the animal a chemotherapeutic dosage of0,0-dimethy1 S-(4-dimethy1amino-6- JULIAN LEVITT, PrlmaryExammeramino-1,3,5-triazin-2-yl)methyl phosphorothioate. FRANKCACCIAPAGLIA, m, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,192,109

June 29, 196.

Robert L. Goulding, Jr., et a1. It is hereby certified that error a entrequiring correct corrected below.

ppears in the above numbered pation and that the said Letters Patentshould read as Column 1, line 19, for "screws-worms" read worms column2, line 69, for "on aqueous an aqueous emulsion column 4, line 24,insert flea same column 4, line 71, ate" read phosphorodithioatescrewemulsion" read before "mortality" for "phosphorothio- Signed andsealed this 21st day of December 1965 (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

2. A METHOD FOR CONTROLLING INSECTS AND HELMINTHS ATTACKING DOMESTIC WARM-BLOODED ANIMALS, WHICH COMPRISES INTRODUCING INTO THE BODY OF THE ANIMAL A CHEMOTHERAPEUTIC DOSAGE OF A COMPOUND OF THE FOLLOWING FORMULA: 